Organophosphate (OP) nerve agents represent a threat to military personnel and civilians. In order to avoid a cholinergic crisis due to permanent binding of the nerve agent to acetylcholinesterase (ACHE) and the accumulation of acetylcholine (Ach) in the synaptic cleft, a reactivator such as 2-pyridine aldoxime methyl chloride (2-PAM Cl) must be delivered to debind the organophosphate from the enzyme within minutes of exposure. In addition, effective treatment may involve the delivery of another active pharmaceutical ingredient (API), such as a competitive inhibitor (e.g., atropine sulfate-ATR) of the muscarinic receptor, antagonizing the action of excess Ach. 2PAM CL and ATR may therefore provide a synergistic effect when injected in rapid succession.
Since such drugs must be delivered within minutes of OP exposure, autoinjectors are preferred. An autoinjector may be understood herein as a medical device designed to deliver a dose of a particular drug and typical autoinjectors are spring-loaded syringes which are intended for self-administration by a patient. Commercially available autoinjectors can deliver, e.g., 2 mL, 1 mL and 0.7 mL of liquid.
Reference is made to Canadian Patent Application No. 689384 entitled “Method For Producing 2-Pyridinealdoxime Methochloride.” A method of preparation of 2-pyridinealdoxime methochloride is disclosed and it is reported that such compound occurs as a white crystalline powder which is soluble in water to the extent of one gram in less than one cc.
Accordingly, a need remains for a relatively stable aqueous suspension of oxime compounds, optionally combined with another API, suitable for treatment of exposure to OP nerve agents. More specifically a need remains for aqueous suspensions of oximes which can provide one dose of 600 mg of the oxime compound in aqueous suspension contained in a 1.0 mL or smaller autoinjector device, along with requisite shelf-life stability.